The long-term objective of this research program is to determine the mechanistic bases and consequences of temporally correlated activity in the hippocampal formation, a brain region that is crucial for the formation of episodic memories. The proposed work focuses on rate-dependent synaptic efficacy (RDE), a Dhenomenon we discovered in the previous funding period. In RDE, short bouts of paired high-frequency activity in presynaptic Schaffer collaterals and postsynaptic CA1 pyramidal cells lead to a temporary increase n the efficacy of this synapse, as measured by the amplitude of excitatory postsynaptic potentials. Mechanistically, RDE arises in a surprising manner: high-frequency pre- and postsynaptic activity relieves heretofore undescribed suppression of synaptic efficacy by presynaptic or postsynaptic glycine receptors. In the proposed work, we will characterize RDE in terms of its magnitude, kinetics, and the degree to which nduction of RDE at one synapse affects synaptic efficacy at other synapses onto the same postsynaptic neuron (Aim 1). We will follow up on intriguing results suggesting that hippocampal bistratified GABAergic nterneurons may also give rise to glycinergic terminals in region CA1 (Aim 2). We will extend our mechanistic studies of RDE to understand the important underlying events and signaling mechanisms (Aim 3). Finally, we will explore the implications of RDE for long-term synaptic plasticity (Aim 4), testing the hypothesis that rate-dependent synaptic efficacy contributes to the rate-dependence of long-term synaptic plasticity. Lay description: This proposal focuses on the synaptic interactions between nerve cells that are responsible for memory formation. In particular, we propose to study how neural activity leads to short-term changes in the degree to which nerve cells influence each other via chemical synapses, as well as how these short-term changes may influence the formation of long-term memories. The emphasis is on mechanistic descriptions that will be useful in devising new treatments for memory disorders. Because this work will further our understanding of how high-rate neuronal activity is amplified further by the synapse, it may provide insights into diseases involving runaway excitation (e.g. temporal lobe epilepsy).